Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons
Yan Rao, … , Tamas L. Horvath, Xiao-Bing Gao
Yan Rao, … , Tamas L. Horvath, Xiao-Bing Gao
Published December 3, 2007
Citation Information: J Clin Invest. 2007;117(12):4022-4033. https://doi.org/10.1172/JCI32829.
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Research Article

Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons

Abstract

Sleep is a natural process that preserves energy, facilitates development, and restores the nervous system in higher animals. Sleep loss resulting from physiological and pathological conditions exerts tremendous pressure on neuronal circuitry responsible for sleep-wake regulation. It is not yet clear how acute and chronic sleep loss modify neuronal activities and lead to adaptive changes in animals. Here, we show that acute and chronic prolonged wakefulness in mice induced by modafinil treatment produced long-term potentiation (LTP) of glutamatergic synapses on hypocretin/orexin neurons in the lateral hypothalamus, a well-established arousal/wake-promoting center. A similar potentiation of synaptic strength at glutamatergic synapses on hypocretin/orexin neurons was also seen when mice were sleep deprived for 4 hours by gentle handling. Blockade of dopamine D1 receptors attenuated prolonged wakefulness and synaptic plasticity in these neurons, suggesting that modafinil functions through activation of the dopamine system. Also, activation of the cAMP pathway was not able to further induce LTP at glutamatergic synapses in brain slices from mice treated with modafinil. These results indicate that synaptic plasticity due to prolonged wakefulness occurs in circuits responsible for arousal and may contribute to changes in the brain and body of animals experiencing sleep loss.

Authors

Yan Rao, Zhong-Wu Liu, Erzsebet Borok, Rebecca L. Rabenstein, Marya Shanabrough, Min Lu, Marina R. Picciotto, Tamas L. Horvath, Xiao-Bing Gao

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Figure 2

Experience-dependent synaptic plasticity in mice chronically exposed to prolonged wakefulness.

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Experience-dependent synaptic plasticity in mice chronically exposed to ...
(A) Measurement of locomotor activity indicates development of behavioral sensitization in mice chronically treated with modafinil. Each point represents averaged beam breaks in a 30-minute session from all mice in each group. (B) Sample traces of mEPSCs recorded in hypocretin/orexin neurons from mice chronically treated with saline or modafinil 1 day after the completion of the 7-day treatment. (C) Pooled data from all recorded neurons in control mice and mice chronically exposed to prolonged wakefulness indicate the potentiated frequency of mEPSCs in modafinil-treated mice. *P < 0.05, Student’s t test. (D) Pooled data from all recorded neurons in control mice and mice chronically exposed to wakefulness indicate the potentiated amplitude of mEPSCs in modafinil-treated mice. *P < 0.05, Student’s t test. (E) Cumulative probability of the amplitude of mEPSCs recorded from mice treated with modafinil (4,163 events) or saline (3,232 events). The rightward shift of cumulative distribution of mEPSC amplitude in the modafinil-treated group was significant (P < 0.001, Kolmogorov-Smirnov test). (F and G) Chronic treatment with modafinil increases the number of asymmetric (putative excitatory) synapses on perikarya containing hypocretin/orexin (Hcrt). (F) Electron micrographs of asymmetric (putative excitatory) synapses on hypocretin/orexin-containing perikarya in saline- (left) or modafinil-treated mice (right). Presynaptic terminals are indicated by the asterisk. Scale bar: 1 μm. (G) Bar graph shows the numbers of asymmetric synapses per 100 μm perikaryal membrane of hypocretin neurons in saline- or modafinil- treated mice. *P < 0.05.